The mechanisms by which analogs and antagonists of the dicarboxylic amino acids and their amides exert toxic and oncolytic effects have been examined with animals, cells and isolated enzymes. PALA, an analog of L-aspartic acid, and inhibitor of pyrimidine biosynthesis was shown to have enzymic and pharmacologic properties in the plasma and leukocytes of man comparable to those measured in lower animals. In mice, it was demonstrated that the protracted terminal half-life of PALA may be explained by its long-lived sequestration in bone. L-Alanosine, also an analog of L-aspartic acid, interrupts purine biosynthesis only after complex anabolism; the principal enzyme responsible for such anabolism was measured in tumors sensitive and resistant to the drug; in only one case did depression of the activities of SAICAR synthetase correlate with resistance. Lastly the biochemical basis for the augmented CI toxicity in female mice of chloroisoxazole, a new L-glutamine antagonist was examined. The specific activities of the amidotransferases known to be targets of this drug were increased in the jejenum of females but inhibition of these enzymes achieved by therapeutic doses of chloroisoxazole were also greater in this sex.